This proposal represents the first resubmission of the new application NIMH MH-0708060-01, which requests 5 years of funding for the grant entitled "Treatment for Bipolar Depression: Acute &Prophylactic Efficacy with Citalopram." The primary hypothesis to be tested relates to a randomized clinical trial into antidepressant efficacy in bipolar depression. The applicant will study the impact of a serotonin reuptake inhibitor (SRI), citalopram, added to standard mood stabilizers in a double-blind, placebo- controlled, randomized fashion for 6 week acute efficacy, along with 1 year maintenance efficacy. In addition, the application seeks to acquire novel knowledge about the pathophysiology of depression in bipolar disorder using measures of genomics and functional neuroimaging, and, for the first time, biological predictors of treatment response as well as adverse outcomes with antidepressants (such as mania). The proposal follows up on completion of a R23 award to the principal investigator on long-term antidepressant outcome in bipolar disorder. Rationale: In contrast to unipolar major depression, bipolar depression is among the least studied depressive illnesses, with very little research on the short- and long-term efficacy or safety of antidepressants used in conjunction with mood-stabilizing agents, or their effect on the course of bipolar disorder. Previous studies have identified possible risks of sustained treatment with antidepressants in bipolar disorder, including induction of mania, mixed states, psychosis, or rapid-cycling. Despite these potential risks, the depressive phase of bipolar disorder is sufficiently compelling clinically that antidepressants rather than mood-stabilizing agents are the most commonly used treatments in bipolar disorder, supporting the timeliness of the present proposal. It is unknown if these antidepressant treatments are effective or even safe in these circumstances. Further, while functional neuroimaging and genetic predictors of response with antidepressants have been studied in unipolar depression, similar mechanisms in bipolar depression are largely unknown. Public Health Implications: Bipolar depression is a virulent mood disorder, with a high suicide rate and marked loss of work and social productivity. Antidepressants are commonly used, making it essential to know if they should be used extensively as they are, or whether their use should be more restricted;yet there is little to no rigorous scientific evidence regarding their efficacy and safety in bipolar depression. Especially given suggestions that some patients may markedly worsen with antidepressants, better understanding of when to use, and when not to use, antidepressants in bipolar disorder is a major public health concern.